Microfluidic device, system, and method for reversing a flow through a microfluidic channel

ABSTRACT

There is provided a microfluidic device for reversing a flow through a microfluidic channel. The microfluidic device comprises a first microfluidic channel extending between a first inlet and a first outlet, a second microfluidic channel which fluidically connects a first point of the first microfluidic channel to a second outlet via a first valve, a third microfluidic channel which fluidically connects a second point of the first microfluidic channel to a second inlet via a second valve, the second point being located between the first point and the first outlet, and at least one circuit for opening the first valve and the second valve. The first and the second valves are arranged to be initially closed, Upon opening of the first and the second valve during use, the flow direction through the first microfluidic channel between the first point and the second point is reversed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.16/267,542, filed on Feb. 5, 2019, which claims priority to EuropeanPatent Application No. 18155088.0, filed on Feb. 5, 2018, the entiredisclosure of each of which are incorporated herein by reference.

TECHNICAL FIELD

The present disclosure relates to a microfluidic device and amicrofluidic system for reversing a flow through a microfluidic channel.The disclosure also relates to a method for reversing a flow through amicrofluidic channel using the microfluidic system, and a diagnosticdevice comprising the microfluidic device.

BACKGROUND

Microfluidics deals with the behavior, precise control and manipulationof fluids that are geometrically constrained to a small, typicallysub-millimeter, scale. Technology based on microfluidics are used forexample in ink-jet printer heads, DNA chips and within lab-on-a-chiptechnology. In microfluidic applications, fluids are typically moved,mixed, separated or otherwise processed. In many applications, passivefluid control is used. This may be realized by utilizing the capillaryforces that arise within the sub-millimeter tubes. By carefulengineering of a so called capillary driven fluidic system, it may bepossible to perform control and manipulation of fluids.

In some applications of microfluidics, it may be desirable to reversethe flow of fluid through a microfluidic channel. An example of such anapplication is cell purification where cells or microparticles are to beseparated from other material in a sample fluid. For that purpose themicrofluidic channel may include a cell trapping structure which trapsor captures cells or microparticles when fluid flow is in a firstdirection and releases the cells when the fluid flow direction isreversed.

There is thus a need for microfluidic devices which allows for reversinga fluid flow through a microfluidic channel.

SUMMARY

Example embodiments provides a microfluidic device for reversing a flowthrough a microfluidic channel. The microfluidic device comprises afirst microfluidic channel extending between a first inlet and a firstoutlet, a second microfluidic channel which fluidically connects a firstpoint of the first microfluidic channel to a second outlet via a firstvalve, a third microfluidic channel which fluidically connects a secondpoint of the first microfluidic channel to a second inlet via a secondvalve, the second point being located between the first point and thefirst outlet, and at least one circuit for opening the first valve andfor opening the second valve. The first and the second valves arearranged to be initially closed, thereby causing fluid to initially flowin a first direction in the first microfluidic channel from the firstinlet to the first outlet during use. However, upon opening both thefirst and second valves during use, the flow direction through the firstmicrofluidic channel between the first point and the second point isreversed, and fluid flows from the second inlet via the firstmicrofluidic channel to the second outlet.

BRIEF DESCRIPTIONS OF THE DRAWINGS

The above, as well as additional objects, features and advantages, willbe better understood through the following illustrative and non-limitingdetailed description of embodiments described herein, with reference tothe appended drawings, where the same reference numerals will be usedfor similar elements, wherein:

FIGS. 1-4 illustrate a microfluidic system for reversing a flow througha microfluidic channel according to various embodiments.

FIG. 5 is a flow chart of a method for reversing a flow through amicrofluidic channel according to embodiments.

FIG. 6A illustrates a forward flow condition in the microfluidic systemaccording to embodiments, and

FIG. 6B illustrates a reverse flow condition in the microfluidic systemaccording to embodiments.

DETAILED DESCRIPTION

In view of the above, it is an object to provide a microfluidic device,a system, and a method which allows for reversing a fluid flow through amicrofluidic channel.

According to a first aspect, there is provided a microfluidic device forreversing a flow through a microfluidic channel, comprising:

a first microfluidic channel extending between a first inlet and a firstoutlet,

a second microfluidic channel which fluidically connects a first pointof the first microfluidic channel to a second outlet via a first valve,

a third microfluidic channel which fluidically connects a second pointof the first microfluidic channel to a second inlet via a second valve,the second point being located between the first point and the firstoutlet,

wherein the first valve and the second valve are arranged to beinitially closed to prevent fluid from the first microfluidic channel toreach the second outlet and the second inlet, respectively, such that,during use, fluid initially flows in the first microfluidic channel in afirst direction from the first inlet to the first outlet, and

at least one circuit for opening the first valve and for opening thesecond valve,

wherein, upon the at least one circuit opening the first valve and thesecond valve during use, a flow direction through the first microfluidicchannel between the first point and the second point is reversed fromthe first direction to a second direction as fluid flows from the secondinlet via the first microfluidic channel to the second outlet.

The first and the second valve are thus arranged to control the flow inthe first, second, and third microfluidic channels. Initially, whenclosed, the first and the second valve stop fluid flow in the second andthe third microfluidic channel, and fluid flow is restricted to thefirst microfluidic channel in the direction from the first inlet to thefirst outlet. However, when the valves are opened as triggered by the atleast one circuit, fluid flow is enabled also in the second and thirdmicrofluidic channels, and a fluid flow from the second inlet to thesecond outlet via the first microfluidic channel is established, therebyreversing the flow direction through the first microfluidic channel.

The first inlet may be any suitable inlet for receiving a fluid. Thefluid may be a sample fluid. The first inlet may hence be a sampleinlet. The sample fluid may, for instance, be a body fluid such asblood, saliva, or urine.

The second inlet may be any suitable inlet for receiving a fluid. Thefluid may be a buffer fluid used in connection to analyzing a samplefluid. The second inlet may hence be a buffer inlet. The buffer fluidmay, for instance, be a saline solution.

The at least one circuit may be any circuit suitable for opening thefirst valve and the second valve. The at least one circuit may be atleast one actuating circuit. The at least one circuit may include afirst circuit for opening the first valve and a second circuit foropening the second valve.

The first and the second outlet may be any suitable outlet to which apump, such as a capillary pump or a vacuum source, may be connected.

A microfluidic channel is any suitable channel having a width and heightbeing measured on a sub-millimeter scale, such as in tens of microns oreven less. The microfluidic channels are typically capillary channels,i.e., having a width and a height being of such dimension that a fluidheld therein is propelled to move forward by means of capillary forces.

The valves may be microfluidic valves, such as, for instance, capillaryvalves. Capillary valves typically stop the advancing liquid-vaporinterface by an abrupt change in geometry that prevents further wettingby the liquid. As an example, the valves may be capillary triggervalves. Such valves are arranged to open up for passage of the fluidentering the valve through a main input upon the valve being reached bya control fluid entering the valve through a separate control input. Asanother example, the valves could be actuated electrically, such asbeing electrically-triggered capillary stop valves. The fluid is thenactuated by using an electrode that advances the liquid-vapor interfacethrough electrostatic forces past the abrupt change in geometry allowingthe liquid vapor interface to proceed further downstream of the valve.

The microfluidic device may further comprise:

a first flow conduit with flow resistance R1 arranged in the firstmicrofluidic channel between the first inlet and the first point, asecond flow conduit with flow resistance R2 arranged in the firstmicrofluidic channel between the second point and the first outlet, athird flow conduit with flow resistance R3 arranged in the secondmicrofluidic channel between the first point and the first valve. Thefirst flow conduit controls the flow rate from the first inlet, thesecond flow conduit controls the flow rate into the first outlet, andthe third flow conduit controls the flow rate into the second outlet.

The flow conduits may generally be flow resistors having flowresistances R1, R2, R3.

The flow resistances of the flow conduits may satisfy the followingcondition:p _(in,buffer)(R ₁ +R ₃)R ₂ −p _(pump,2)(R ₁ R ₂)−p _(in,sample)(R ₂ R₃)−p _(pump,1)(R ₁ +R ₃)R _(C3)>0.

where p_(in,buffer), and p_(in,sample) are capillary pressures at thesecond inlet and the first inlet, respectively, p_(pump,1) andp_(pump,2) are the negative pressures of pumps which during use areconnected to the first outlet and to the second outlet, respectively,and R_(C3) is the flow resistance of the third microfluidic channel.

The above condition on the flow resistances and the pressures is asufficient condition for establishing a reverse flow in the firstmicrofluidic channel as will be demonstrated later.

As mentioned above, one possible application of the microfluidic deviceis to trap particles, such as cells or micro particles, in fluidprovided to the first inlet. For that purpose, the microfluidic devicemay further comprise a particle trap, i.e., a particle trappingstructure, arranged in the first microfluidic channel between the firstpoint and the second point.

For example, the particle trap may be arranged to trap particles if theflow direction through the particle trap is in the first direction. Theparticle trap may further be arranged to release particles if the flowdirection through the particle trap is in the second direction.

The at least one circuit may trigger the first valve to open indifferent ways. In particular, the at least one circuit may be arrangedto trigger the first valve to be opened by using electrical signals orby using fluid from the second inlet. Both these ways of implementingthe at least one circuit enable a design of the microfluidic devicewhich allows the pumps to be off-chip, i.e., to be connected to themicrofluidic device as separate entities.

According to embodiments, the at least one circuit includes a firstmicrofluidic circuit which fluidically connects the first valve to thesecond inlet, such that, during use, the first valve is triggered to beopened as it is reached by fluid from the second inlet via the firstmicrofluidic circuit. In this way, the first valve is hence triggered toopen by using fluid from the second inlet.

According to other embodiments, the at least one circuit includes anelectric circuit configured to electrically trigger the first valve tobe opened. In this way, the first valve is hence triggered to open byusing electrical signals, and no direct fluid passage from the secondinlet to the first valve is needed.

It is to be understood that designs are also possible where the firstvalve is triggered by using fluid from the first inlet. For instance,the at least one circuit may comprise a microfluidic circuit whichprovides a direct fluid connection between the first inlet and the firstvalve (i.e., a fluid connection which is separate from the fluidconnection provided by the first microfluidic channel and the secondmicrofluidic channel). Such a design would also enable the pumps to beoff-chip.

The at least one circuit may trigger the second valve to open by usingfluid from the second inlet. For example, the at least one circuit mayinclude a portion of the third microfluidic channel that fluidicallyconnects the second valve to the second inlet, such that, during use,the second valve is triggered to be opened as it is reached by fluidfrom the second inlet via said portion of the third microfluidicchannel.

With this arrangement, the second valve is thus triggered to open as itis reached by fluid from the second inlet. The timing of the opening ofthe second valve may be achieved in different ways. For example, thetiming may be achieved by adding fluid to the second inlet at a desiredpoint in time, such as at a point in time when it is desirable toreverse the flow in the first microfluidic channel.

However, in some situations it may be advantageous to control the timingautomatically and more precisely. For that purpose, the microfluidicdevice may comprise means, such as a third valve, for controlling theprovision of fluid from the second inlet to the second valve. Morespecifically, the portion of the third microfluidic channel mayfluidically connect the second valve to the second inlet via a thirdvalve which is arranged to be initially closed so as to prevent fluidfrom the second inlet to reach the second valve.

The third valve may be triggered to open in different ways, such as byusing electrical signals or by using fluid from the second inlet. As anexample of the latter, the at least one circuit may further include asecond microfluidic circuit which fluidically connects the third valveto the second inlet, such that, during use, the third valve is triggeredto be opened as it is reached by fluid from the second inlet via thesecond microfluidic circuit. By way of example, the second microfluidiccircuit may be a microfluidic channel interconnecting the second inletand the third valve. The length and dimensions of that microfluidicchannel may be designed such that fluid from the second inlet reaches,and thereby triggers, the third valve after a predetermined time fromentering the channel. As an example, of the former, the microfluidicdevice may further include an electric circuit configured toelectrically trigger the third valve to be opened.

In some applications, the microfluidic device may be used to detectparticles in a fluid. For that purpose, a portion of the secondmicrofluidic channel that fluidically connects the first valve to thesecond pump inlet may include a detection channel for detection ofparticles in a fluid held by the detection channel.

The microfluidic device may have an open design, meaning that themicrofluidic channels are non-covered, and thereby may exchange air withthe surroundings. Alternatively, the microfluidic device may have, atleast partly, a closed design, meaning that at least some (but typicallyall) of the microfluidic channels are covered by an air-tight cover. Assuch a cover prevents air from escaping the microfluidic channels, onemay arrive at a situation where air get trapped in the microfluidicchannels, resulting in problems with triggering the valves. Inparticular, such a problem could occur at the second valve if the thirdmicrofluidic channel is covered. To resolve that issue, when at leastthe third microfluidic channel is provided with an air-tight cover, avent may be connected to the second valve to allow air to escape fromthe second valve.

According to a second aspect, there is provided a microfluidic systemfor reversing a flow through a microfluidic channel, comprising:

a microfluidic device of the first aspect,

a first pump connected to the first outlet, and

a second pump connected to the second outlet.

According to a third aspect, there is provided a method for reversing aflow through a microfluidic channel using the microfluidic system of thesecond aspect, comprising:

providing a sample fluid to the first inlet, thereby establishing aninitial flow of sample fluid in the first microfluidic channel in afirst direction from the first inlet to the first outlet;

providing a buffer fluid to the second inlet; and

opening, using the at least one circuit, the first valve and the secondvalve, thereby reversing a flow direction through the first microfluidicchannel between the first point and the second point from the firstdirection to a second direction as buffer fluid flows from the secondinlet via the first microfluidic channel to the second outlet.

According to a fourth aspect, there is provided a diagnostic devicecomprising the microfluidic device according to the first aspect. Forexample, the microfluidic device may form part of chip or a cartridgeincluded in the diagnostic device for self-diagnostic purposes.

The second, third, and fourth aspects may generally have the samefeatures and advantages as the first aspect. It is further noted thatthe inventive concepts relate to all possible combinations of featuresunless explicitly stated otherwise.

Example embodiments will now be described more fully hereinafter withreference to the accompanying drawings.

FIG. 1 illustrates a microfluidic system 12. The microfluidic system 12includes a microfluidic device 4, a first pump P1, and a second pump P2.The first pump P1 is connected to a first outlet 5 of the microfluidicdevice 4, and the second pump P2 is connected to a second outlet 9 ofthe microfluidic device 4. The first and the second pumps P1, P2 may,for instance, be capillary pumps which are porous structures thatsustains flow by generating a given capillary pressure, or vacuumsources. The pressures generated by the first pump P1 and the secondpump P2 are denoted by p_(pump,1) and p_(pump,2), respectively.

The microfluidic device 4 and the pumps P1, P2 may be separate entities.For example, the microfluidic device 4 may be implemented on a chip,such as a semiconductor or a plastic chip, to which the pumps are P1, P2are connected. Alternatively, the microfluidic device 4 and one or bothof the pumps P1, P2 may be implemented on the same chip. Fabricationmethods for the microfluidic device 4, and the structures thereof, suchas the microfluidic channels, flow resistors, and valves, include, butare not limited to, etching techniques.

The microfluidic device 4 comprises a first microfluidic channel 1 whichextends between a first inlet 7 and the first outlet 5. The firstmicrofluidic channel 1 may be referred to as a primary channel.

The microfluidic device 4 further comprises a second microfluidicchannel 2 a, 2 b. The second microfluidic channel 2 a, 2 b fluidicallyconnects the first microfluidic channel 1 to the second outlet 9 via afirst valve V1. In more detail, the second microfluidic channel 2 a, 2 bcomprises a first portion 2 a which connects a first point CP1 of thefirst microfluidic channel 1 to an inlet of the first valve V1, and asecond portion 2 b which connects an outlet of the first valve V1 to thesecond outlet 9.

The microfluidic device 4 further comprises a third microfluidic channel3 a, 3 b which fluidically connects the first microfluidic channel 1 toa second inlet 8 via a second valve V2. More specifically, the thirdmicrofluidic channel has a first portion 3 a which connects a secondpoint CP2 of the first microfluidic channel 1 to an inlet of the secondvalve V2, and a second portion 3 b which connects an outlet of thesecond valve V2 to the second inlet 8. The second point CP2 is locatedbetween the first point CP1 and the first outlet 5.

Optionally, a particle trap 6, a reaction chamber or similar, dependingon the application, may arranged in the first microfluidic channel 1between the first point CP1 and the second point CP2. The particle trap6 may be arranged to trap particles such as cells or micro particles ina sample provided at the first inlet 7. The particle trap 6 may bearranged to trap particles as a flow direction through the particle trapis in a first direction, from the first inlet to the first outlet 5, andto release particles as a flow direction through the particle trap 6 isin the reverse direction. Many techniques for particle trapping exist,utilizing methods such as optical, acoustic, magnetic,electrohydrodynamic, or purely hydrodynamic forces. Hydrodynamic traps,for example, utilize arrays of structures with constrictions designed totrap particles when flowing in one direction. The structures typicallyallow particles to bypass around the structure once one particle istrapped within the structure so that the trap does not clog. Thestructures may then release the particles once flow is reversed in thetrap with the particles flowing unhindered by the structures in thereverse flow direction. In order to facilitate detection of particles,the portion 2 b of the second microfluidic channel may include adetection channel for detection of particles (as, for instance, releasedfrom the particle trap) in the fluid. Detection of the particles may bethrough, for example, optical or electrical means.

The microfluidic device 4 is a capillary-driven microfluidic network. Inparticular, all channels of the microfluidic device 4, such as thefirst, second, and third microfluidic channels 1, 2 a, 2 b, 3 a, 3 b arecapillary channels, meaning that their traverse cross-sections aresufficiently small to allow capillary forces (a combination of surfacetension and adhesive forces between the liquid fluid and the channelwalls) to propel the fluid held therein.

The microfluidic device 4 may further comprise a first flow conduit withflow resistance R1, a second flow conduit with flow resistance R2, and athird flow conduit with flow resistance R3. The first flow conduit withflow resistance R1 controls the flow rate from the sample input 7, thesecond flow conduit with flow resistance R2 controls the flow rate intothe first outlet 5, and the third flow conduit with flow resistance R3controls the flow rate into the second outlet 9. The flow conduits maybe microfluidic channels of certain cross-sectional dimension and lengthto generate the required resistance. In some embodiments, one or more ofthe flow conduits may be left out. Generally, the flow resistance of thefirst microfluidic channel between points CP1 and CP2 and the flowresistance of the third microfluidic channel 3 a, 3 b are assumed to bemuch smaller than the resistance R1, R2, and R3 of the flow conduits.

Each of the first and the second valve V1, V2 may be in a closedposition and in an open position. When the first valve V1 is in a closedposition it prevents fluid from the first microfluidic channel 1 toreach the second outlet 9. Similarly, when the second valve V2 is in aclosed position it prevents fluid from the first microfluidic channel 1to reach the second inlet 8. Both the first and the second valve V1, V2are arranged to be initially closed, i.e., they are in a closed positionas the microfluidic device 4 is first taken into use. When the firstvalve V1 is in an open position, it allows a flow in the directiontowards the second outlet 9. When the second valve V2, which is aone-way valve, is in an open position, it allows a flow in the directionfrom the second inlet 8 towards the first microfluidic channel 1.

The first and the second valves V1 and V2 may be trigger valves, such ascapillary trigger valves. The trigger valves may be passive, meaningthat they may be passively triggered, such as by means of a fluidtriggering the valve to open, or active, meaning that they are activelytriggered, such as by means of an electrical control signal.

In order to control the opening of the first and the second valve V1,V2, the microfluidic device 4 comprises at least one circuit 11 arrangedto open the first valve V1 and the second valve V2. The at least onecircuit 11 may be arranged to trigger the first valve V1 to be opened byusing electrical signals or by using fluid. The example embodiment ofFIG. 1 is an example of the latter. In more detail, the at least onecircuit 11 includes a first microfluidic circuit T1 which fluidicallyconnects the second inlet 8 to a trigger channel of the first valve V1.The first microfluidic circuit T1 may be a microfluidic channel having acertain cross-sectional dimension and length so that the fluid takes agiven amount of time to traverse the channel. In that way, the timing ofthe opening of the valve V1 may be controlled.

In an alternative embodiment, illustrated in FIG. 2 , the at least onecircuit 11 instead includes an electric circuit C1 configured toelectrically trigger the first valve V1 to open, such as by sending anelectric control signal to the first valve V1. The electric circuit C1may be controlled by a controller 13 configured to generate the electriccontrol signal. The controller 13 may be controlled to generate theelectric control signal after a predetermined amount of time from, forinstance, provision of a sample at the first inlet. In that way, thetiming of the opening of the valve V1 may be controlled. The at leastone circuit 11 is arranged to trigger the second valve V2 to be opened.As shown in the example embodiments of FIGS. 1 and 2 , the second valveV2 may be triggered as fluid from the second inlet 8 reaches the secondvalve V2 via portion 3 b of the third microfluidic channel 3 a, 3 b. Theat least one circuit 11 may thus be said to include the portion 3 b ofthe third microfluidic channel 3 a, 3 b.

The timing of the opening of the second valve V2 as shown in FIGS. 1 and2 is dependent on when a fluid is provided to the second inlet 8. Inorder to be able to more precisely control the opening of the secondvalve V2, the at least one circuit 11 may control the provision of fluidfrom the second inlet 8 to the second valve V2 by using a third valve V3as shown in FIGS. 3 and 4 . More specifically, a third valve V3 isarranged in the portion 3 b of the third microfluidic channel, such thatthe portion 3 b of the third microfluidic channel fluidically connectsthe second valve V2 to the second inlet 8 via the third valve V3.

Similar to the first and the second valves, the third valve V3 may be atrigger valve, such as capillary trigger valve. The trigger valve may bepassive, meaning that it may be passively triggered, such as by means ofa fluid triggering the valve to open, or active, meaning that it isactively triggered, such as by means of an electrical control signal.

The third valve V3 is arranged to be initially closed so as to preventfluid from the second inlet 8 to reach the second valve V2. The at leastone circuit 11 may further be arranged to trigger the third valve V3 tobe opened, e.g., by using electrical signals or by using fluid from thesecond inlet 8. As the third valve V3 is opened, fluid from the secondinlet 8 is allowed to flow to the second valve V2, thereby triggeringthe second valve V2 to be opened.

In the example embodiment of FIG. 3 , the third valve V3 is triggered bymeans of fluid from the second inlet 8. For this purpose, the at leastone circuit 11 includes a second microfluidic circuit T2 which isseparate from the portion 3 b of the third microfluidic channel andwhich fluidically connects a trigger channel of the third valve V3 tothe second inlet 8. As fluid from the second inlet 8 reaches the thirdvalve V3 via the second microfluidic circuit T2, during use, the thirdvalve V3 will be opened, thereby allowing fluid from the second inlet 8to flow through the third valve V3 towards the second valve V2 viachannel 3 b. The second microfluidic circuit T2 may be a microfluidicchannel having a certain cross-sectional dimension and length so thatthe fluid takes a given amount of time to traverse the channel. In thatway, the timing of the opening of the valve V3 (and thus also V2) may becontrolled.

In an alternative embodiment, illustrated in FIG. 4 , the at least onecircuit 11 instead includes a second electric circuit C2 configured toelectrically trigger the third valve V3 to open, such as by sending anelectric control signal to the first valve V3. The electric circuit C2may be controlled by a controller 13 configured to generate the electriccontrol signal. The controller 13 may be controlled to generate theelectric control signal after a predetermined amount of time from, forinstance, provision of a sample at the first inlet. In that way, thetiming of the opening of the valve V3 may be controlled.

The controller 13 may be implemented in software or hardware, or acombination thereof. For example, it may include a processor, such as amicroprocessor, which in association with a non-transitorycomputer-readable storing computer code instructions is arranged tocontrol the electric circuit C1 and/or C2 to open the first and/or thesecond valve V1, V2 to open. Alternatively, or additionally, thecontroller 13 may include circuitry, such as an integrated circuit, afield programmable gate array (FPGA) or similar, specifically designedfor the purpose of controlling the electric circuit C1 and/or C2 to openthe first and/or the second valve V1, V2 to open.

In the example embodiment of FIG. 3 both the first valve V1 and thethird valve V3 are actuated to open by using fluid from the second inlet8, and in the example embodiment of FIG. 4 both the first valve V1 andthe third valve V3 are actuated to open by using electrical signals.However, it is to be understood that these embodiments may be combinedsuch that one of first and the third valve V1, V3 is actuated by usingelectrical signals, and the other by using fluid from the second inlet.Embodiments may also be envisaged where one, or both, of the first valveV1 and the third valve V3 are actuated by using fluid from the firstinlet (i.e., the first microfluidic circuit T1, may instead interconnectthe first valve V1 with the first inlet 7 and/or the second microfluidiccircuit T2 may interconnect the second valve V2 with the first inlet 7).

Any of the example embodiments may have an open or a closed design,meaning that the microfluidic device 4 and the channels thereof eitherhave an open top surface, thereby allowing air to escape from thechannels, or a covered top surface, thereby preventing air to escapefrom the channel. In the latter case, there is a risk of air beingtrapped in the channels. In particular, there is a risk that air istrapped in the third microfluidic channel 3 a, 3 b at the second valveV2. If that happens, the trapped air may prevent fluid from the secondinlet 8 to reach the second valve V2, thereby preventing the secondvalve from being opened. In order to allow air to escape, the secondvalve V2 may be provided with a vent 10, such as a vent hole, whichallows air to escape.

A method for reversing a flow through the first microfluidic channel 1using the microfluidic system described above will now be described withreference to FIGS. 1-4 , and the flow chart of FIG. 5 .

In step S02, a sample fluid, such as blood, urine or similar, isprovided to the first inlet 7. Upon provision of sample fluid to thefirst inlet 7, capillary forces in the first microfluidic channel 1causes the sample fluid to be drawn into the first flow conduit withflow resistance R1. Upon reaching the first point CP1, the flow splitsand proceeds simultaneously through the third flow conduit with flowresistance R3 located in the portion 2 a of the second microfluidicchannel and the first microfluidic channel 1 toward the second pointCP2. After the sample fluid fills the third flow conduit with flowresistance R3, the flow is stopped by the first valve V1 which is in itsclosed position. The flow continues in the first microfluidic channel 1until it reaches the second point CP2. Upon reaching the second pointCP2, the flow splits and proceeds simultaneously into the portion 3 a ofthe third microfluidic channel and into the second flow conduit withflow resistance R2. The sample fluid fills the portion 3 a of the thirdmicrofluidic channel until it reaches the second valve V2 which is inits closed position. Further, after filling the second flow conduit withflow resistance R2, the sample fluid flows into the first capillary pumpP1, which sustains a flow for a given period of time.

Meanwhile, buffer fluid, such as a saline solution, is provided to thesecond inlet 8. In case the microfluidic system has the design shown inFIGS. 3 and 4 , the buffer fluid fills up the portion of the thirdmicrofluidic channel extending between the second inlet 8 until itreaches the third valve V3 which is in its closed position. In case themicrofluidic system has the design shown in FIGS. 1 and 2 , the bufferfluid proceeds towards the second valve V2.

In step S06, the first and the second valve V1, V2 are opened by usingthe at least one circuit 11. In case the microfluidic system has thedesign of FIG. 1 or 2 , the second valve V2 is opened as the bufferfluid reaches the second valve V2 through the portion 3 b or the thirdmicrofluidic channel. In case the microfluidic system has the design ofFIG. 3 or 4 , the third valve V3 is actuated to open by means of thesecond microfluidic circuit T2 or the second electric circuit C2 after adesired time has elapsed. Once the third valve V3 has been opened, theflow proceeds in the portion 3 b of the third microfluidic channel untilit reaches the second valve V2, thereby triggering the second valve V2to open. Meanwhile, the first valve V1 is opened by means of the firstmicrofluidic circuit T1 shown in FIGS. 1 and 3 , or by means of thefirst electric circuit C1. The mutual timing of the of the opening ofthe first and the second valve V1, V2 is not important, since a reverseflow is not established until both the first and the second valve V1, V2have been opened. Once both the first and the second valve V1, V2 havebeen opened, the flow of buffer fluid proceeds through the portion 3 aof the third microfluidic channel, via the first and the secondmicrofluidic channel 1, 2 a, 2 b into the second pump P2.

FIG. 6A illustrates the flow direction of the flow in the firstmicrofluidic channel when the first and the second valves V1 and V2 areclosed. The nodal pressure at the first inlet is denoted byp_(in,sample). The p_(in,sample) may be equal to 0 gauge pressure, i.e.equal to atmospheric pressure. The pressure of the first pump P1 isdenoted p_(pump,1), which is a negative pressure, i.e., belowatmospheric pressure. In other words, p_(in,sample)>p_(pump,1). Sincethe flow stops at valves V1 and V2, there is no flow through the thirdflow conduit with resistance R3 and the channel 3 a. The flow in thefirst capillary channel 1 proceeds from high pressure to low pressure,i.e., in the direction from the first inlet 7 to the first outlet 5 asindicated by the arrow in FIG. 6A since p_(in,sample)>p_(pump,1). Inother words, flow in channel 1 proceeds from CP1 towards CP2 in a firstdirection.

FIG. 6A illustrates the flow direction of the flow in the firstmicrofluidic channel 1 between points CP1 and CP2 when the first and thesecond valves V1 and V2 are open. The nodal pressure at the end ofchannel 3 b is equal to the pressure at the second inlet 8 and isdenoted by p_(in,buffer). The p_(in,buffer) may be equal to 0 gaugepressure, i.e. equal to atmospheric pressure. Further the nodal pressureat the end of channel 2 b is equal to the pressure of the second pump P2and is denoted by p_(pump,2), which is a negative pressure, i.e., belowatmospheric pressure. This induces a reverse flow condition in the firstmicrofluidic channel 1 between points CP1 and CP2. It also induces aflow from the first inlet 7 into the capillary pump P2. This flow can bemitigated by increasing the resistance R1 of the first flow conduit. Aflow is also induced from the second inlet 8 into capillary pump P1.This flow can be mitigated by increasing the resistance R2 of the secondflow conduit.

The following equations describe the flows in the microfluidic device 4when the first and the second valves V1 and V2 are open. Generally, Qdenotes a flow, p denotes a pressure, and R describes a flow resistance.The flow Q₁ through the first flow conduit with resistance R₁ isdescribed given by:p _(in,sample) −p _(CP1) =R ₁ Q ₁,where p_(CP1) is the pressure at point CP1. The flow Q₁ through thefirst microfluidic channel 1 between points CP1 and CP2 is described by:p _(CP2) −p _(CP1) =R _(C1) Q _(C1),where p_(CP2) is the pressure at point CP2 and R_(C1) is the flowresistance of the first microfluidic channel between points CP1 and CP2.The flow Q₃ through the third flow conduit with flow resistance R₃ isdescribed by:p _(CP1) −p _(pump,2)=(R ₃ +R _(C2b))Q ₃,where R_(C2b) is the flow resistance in portion 2 b of the secondmicrofluidic channel. The flow Q₂ through the second flow conduit withflow resistance R₂ is described by:p _(CP2) −p _(pump,1) =R ₂ Q ₂The flow Q_(C3) in the third microfluidic channel 3 a, 3 b is describedby:p _(in,buffer) −p _(CP2) =R _(C3) Q _(C3)where R_(C3) is the flow resistance in the third microfluidic channel 3a, 3 b. Further, the following equations regarding the split of theflows at points CP1 and CP2 should be fulfilled:Q ₁ +Q _(C1) =Q ₃Q _(C1) +Q ₂ =Q _(C3)Solving for the flow Q_(C1) gives:

$Q_{C1} = \frac{\begin{matrix}{{p_{{in},{buffer}}\left( {{R_{1}R_{2}} + {R_{2}R_{3}} + {R_{2}R_{C2b}}} \right)} -} \\{{p_{{pump},2}\left( {{R_{1}R_{2}} + {R_{1}R_{C3}}} \right)} -} \\{{p_{{in},{sample}}\left( {{R_{2}R_{3}} + {R_{3}R_{C3}} + {R_{2}R_{C2b}} + {R_{C3}R_{C2b}}} \right)} +} \\{p_{{pump},1}\left( {{R_{1}R_{C3}} + {R_{3}R_{C3}} + {R_{C3}R_{C2b}}} \right)}\end{matrix}}{\begin{matrix}{{R_{1}R_{2}R_{3}} + {R_{1}R_{2}R_{C1}} + {R_{1}R_{2}R_{C3}} +} \\{{R_{2}R_{3}R_{C1}} + {R_{1}R_{3}R_{C3}} + {R_{1}R_{2}R_{C2b}} +} \\{{R_{2}R_{3}R_{C3}} + {R_{1}R_{C1}R_{C3}} + {R_{3}R_{C1}R_{C3}} +} \\{{R_{2}R_{C1}R_{C2b}} + {R_{1}R_{C3}R_{C2b}} + {R_{2}R_{C3}R_{C2b}} + {R_{C1}R_{C3}R_{C2b}}}\end{matrix}}$The reverse flow condition is satisfied if Q_(C1)>0 so thatp _(in,buffer)(R ₁ R ₂ +R ₂(R ₃ +R _(C2b)))−p _(pump,2)(R ₁(R ₂ +R_(C3)))−p _(in,sample)(R ₂ +R _(C3))(R ₃ +R _(C2b))+p _(pump,1)(R ₁ R_(C3) +R _(C3)(R ₃ +R _(C2b)))>0.Assuming that:R _(C2b) <<R ₃R _(C3) <<R ₂then the inequality can be simplified to:p _(in,buffer)(R ₁ +R ₃)R ₂ −p _(pump,2)(R ₁ R ₂)−p _(in,sample)(R ₂ R₃)+p _(pump,1)(R ₁ +R ₃)R _(C3)>0.The above simplified inequality thus gives a sufficient condition,expressed in terms of flow resistances and pressures for having areverse flow in the first microfluidic channel 1 between points CP1 andCP2 as the first and the second valves V1 and V2 are opened.

As further mentioned above, the purpose of resistance R₃ is to controlthe flow rate into the first pump P1. During forward flow operation, thesum of resistances R1+R2 influences the flow rate through the firstmicrofluidic channel 1 between points CP1 and CP2, i.e., throughparticle trap 6 if available, according top_(in,sample)−p_(pump,1)=(R₁+R₂)Q_(C1). The purpose of R3 is to controlthe flow rate into the second pump P2 during reverse flow operation. Theresistance R1 acts to limit the amount of sample flow from the firstinlet 7 from flowing into the portion 2 b of the second microfluidicchannel, which may serve as a detection channel.

To illustrate, for a target flow rate through the particle trap 6 of 1μL/min in the first direction and using pumps P1, P2 with pressures of−3 kPa (assuming p_(in,sample) and p_(in,buffer) being at 0 gaugepressure) then R1+R2=3 kPa*min/μL.

For R1 much greater than the flow resistances R_(C1) and R_(C3) of thefirst and the third microfluidic channels, the flow rate through theparticle trap in reverse flow condition is largely independent on theprecise value of R₂, assuming a fixed value of R3. In this case, toreach a target flow rate of 1 μL/min in reverse flow condition, R3should approximately be 3 kPa*min/μL (equivalent to a channel 50 μm wideby 50 μm high by 39.5 mm long, for reference). However, during reverseflow condition, it is generally desired to have a low flow rate comingfrom the first inlet 7 compared to the flow rate through the particletrap 6 (to minimize polluting the released particles from the trap withthe sample) To minimize this flow rate, there is an optimum relationbetween R1 and R2, namely R1=R2. R1 and R2 should thus approximatelyboth be equal to 1.5 kPa*min/μL in this example. For R3=3 kPa*min/μL,the resulting flow rate from the first inlet is approximately 3 nL/min(i.e., much lower than the flow rate through the particle trap 6).

If, on the other hand, R1 is much smaller than R2 and R3, and comparablein size to the flow resistances R_(C1) and R_(C3) of the first and thethird microfluidic channels, the amount of sample fluid flowing throughthe portion 2 b of the second microfluidic channel, which may serve as adetection channel, increases drastically. Again, for a target reverseparticle trap flow rate of 1 μL/min, R3 is approximately 0.8 kPa*min/μL,while the flow rate from the first inlet 7 in the second microfluidicchannel is about 3 μL/min. Reverse flow is still achievable under thisconditions but depending on the application, the high sample flow raterelative to the particle trap flow rate may or may not be acceptable.

The embodiments herein are not limited to the above described examples.Various alternatives, modifications and equivalents may be used.Therefore, this disclosure should not be limited to the specific formset forth herein. This disclosure is limited only by the appended claimsand other embodiments than the mentioned above are equally possiblewithin the scope of the claims.

The invention claimed is:
 1. A microfluidic device for reversing a flowthrough a microfluidic channel, comprising: a first microfluidic channelextending between a first inlet and a first outlet; a secondmicrofluidic channel which fluidically connects a first point of thefirst microfluidic channel to a second outlet via a first valve; a thirdmicrofluidic channel which fluidically connects a second point of thefirst microfluidic channel to a second inlet via a second valve, thesecond point being located between the first point and the first outlet;wherein the first valve and the second valve are configured to beinitially closed to prevent fluid from the first microfluidic channel toreach the second outlet and the second inlet, respectively, such that,during use, fluid initially flows in the first microfluidic channel in afirst direction from the first inlet to the first outlet; and at leastone circuit configured to open the first valve and configured to openthe second valve; wherein the at least one circuit is configured totrigger the first valve to be opened by using electrical signals;wherein, upon the at least one circuit opening the first valve and thesecond valve during use, a flow direction through the first microfluidicchannel between the first point and the second point is reversed fromthe first direction to a second direction as fluid flows from the secondinlet via the first microfluidic channel to the second outlet.
 2. Themicrofluidic device according to claim 1, further comprising: a firstflow conduit with flow resistance R1 arranged in the first microfluidicchannel between the first inlet and the first point, a second flowconduit with flow resistance R2 arranged in the first microfluidicchannel between the second point and the first outlet, a third flowconduit with flow resistance R3 arranged in the second microfluidicchannel between the first point and the first valve, wherein the firstflow conduit controls the flow rate from the first inlet, the secondflow conduit controls the flow rate into the first outlet, and the thirdflow conduit controls the flow rate into the second outlet.
 3. Themicrofluidic device according to claim 2, wherein the flow resistanceR1, the flow resistance R2, and the flow resistance R3 meet thefollowing condition:p _(in,buffer)(R ₁ +R ₃)R ₂ −p _(pump,2)(R ₁ R ₂)−p _(in,sample)(R ₂ R₃)−p _(pump,1)(R ₁ +R ₃)R _(C3)>0. where p_(in,buffer), andp_(in,sample) are capillary pressures at the second inlet and the firstinlet, respectively, p_(pump,1) and p_(pump,2) are the negativepressures of pumps which during use are connected to the first outletand to the second outlet, respectively, and R_(C3) is the flowresistance of the third microfluidic channel.
 4. The microfluidic deviceaccording to claim 1, further comprising a particle trap arranged in thefirst microfluidic channel between the first point and the second point,wherein the particle trap is configured to trap particles in the fluidas a flow direction through the particle trap is in the first direction.5. The microfluidic device according to claim 4, wherein the particletrap is further configured to release particles as a flow directionthrough the particle trap is in the second direction.
 6. Themicrofluidic device according to claim 1, wherein the at least onecircuit includes a first microfluidic circuit which fluidically connectsthe first valve to the second inlet, such that, during use, the firstvalve is triggered to be opened as it is reached by fluid from thesecond inlet via the first microfluidic circuit.
 7. The microfluidicdevice according to claim 1, wherein the at least one circuit includesan electric circuit configured to electrically trigger the first valveto be opened.
 8. The microfluidic device according to claim 1, whereinthe at least one circuit includes a portion of the third microfluidicchannel that fluidically connects the second valve to the second inlet,such that, during use, the second valve is triggered to be opened as itis reached by fluid from the second inlet via said portion of the thirdmicrofluidic channel.
 9. The microfluidic device according to claim 8,wherein the portion of the third microfluidic channel fluidicallyconnects the second valve to the second inlet via a third valve which isconfigured to be initially closed so as to prevent fluid from the secondinlet to reach the second valve.
 10. The microfluidic device accordingto claim 9, wherein the at least one circuit further includes a secondmicrofluidic circuit which fluidically connects the third valve to thesecond inlet, such that, during use, the third valve is triggered to beopened as it is reached by fluid from the second inlet via the secondmicrofluidic circuit.
 11. The microfluidic device according to claim 1,wherein the at least one circuit further includes an electric circuitconfigured to electrically trigger the third valve to be opened.
 12. Themicrofluidic device according to claim 1, wherein at least the thirdmicrofluidic channel is provided with an air-tight cover, and a vent isconnected to the second valve to allow air to escape from the secondvalve.